NEDD8 nucleates a multivalent cullin–RING–UBE2D ubiquitin ligation assembly

Kheewoong Baek, David T. Krist, J. Rajan Prabu, Spencer Hill, Maren Klügel, Lisa-Marie Neumaier, Susanne Gronau, Gary Kleiger and Brenda A. Schulman ()
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Kheewoong Baek: Max Planck Institute of Biochemistry
David T. Krist: Max Planck Institute of Biochemistry
J. Rajan Prabu: Max Planck Institute of Biochemistry
Spencer Hill: University of Nevada, Las Vegas
Maren Klügel: Max Planck Institute of Biochemistry
Lisa-Marie Neumaier: Max Planck Institute of Biochemistry
Susanne Gronau: Max Planck Institute of Biochemistry
Gary Kleiger: University of Nevada, Las Vegas
Brenda A. Schulman: Max Planck Institute of Biochemistry

Nature, 2020, vol. 578, issue 7795, 461-466

Abstract: Abstract Eukaryotic cell biology depends on cullin–RING E3 ligase (CRL)-catalysed protein ubiquitylation1, which is tightly controlled by the modification of cullin with the ubiquitin-like protein NEDD82–6. However, how CRLs catalyse ubiquitylation, and the basis of NEDD8 activation, remain unknown. Here we report the cryo-electron microscopy structure of a chemically trapped complex that represents the ubiquitylation intermediate, in which the neddylated CRL1β-TRCP promotes the transfer of ubiquitin from the E2 ubiquitin-conjugating enzyme UBE2D to its recruited substrate, phosphorylated IκBα. NEDD8 acts as a nexus that binds disparate cullin elements and the RING-activated ubiquitin-linked UBE2D. Local structural remodelling of NEDD8 and large-scale movements of CRL domains converge to juxtapose the substrate and the ubiquitylation active site. These findings explain how a distinctive ubiquitin-like protein alters the functions of its targets, and show how numerous NEDD8-dependent interprotein interactions and conformational changes synergistically configure a catalytic CRL architecture that is both robust, to enable rapid ubiquitylation of the substrate, and fragile, to enable the subsequent functions of cullin–RING proteins.

Date: 2020
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DOI: 10.1038/s41586-020-2000-y

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